This invention relates to the synthesis of cyclic peptides, and more particularly to a novel method for the synthesis of substituted and unsubstituted 2,5-diketopiperazines.
2,5-Diketopiperazines are useful as fungicides and as intermediates for the synthesis of other compounds. Thus, for example Chan et al, U.S. Pat. No. 4,140,791 discloses the use of 1,4-di(2,6-dimethylphenyl)-2,5-diketopiperazine for control of various fungal disease. Sut et al "N-Monoalkylation of some 2-Oxo and 2,5-Dioxopiperazines", Chimie Therapeutique, 4 (3), pp. 167-173 (1969), describes the synthesis of a series of 2-oxopiperazine and 2,5-dioxopiperazines which were found to have analgesic and anesthetic activities.
The copending and coassigned applications of Miller and Taylor, Ser. No. 778,818 filed Sept. 23, 1985 Miller, Reitz and Pulwer Ser. No. 178,958, filed Sept. 23, 1985 describe the use of 1,4-disubstitued 2,5-diketopiperazines in a synthesis scheme leading to the preparation of N-phosphonomethylglycine. N-phosphonomethylglycine, known also by its common name, glyphosate, is a highly effective and commercially important phytotoxicant useful in controlling a large variety of weeds. It is applied to the foliage of a very broad spectrum of perennial and annual grasses and broadleaf plants. Industrial uses include control of weeds along roadsides, waterways, transmission lines, storage areas, and other non-agricultural areas. Usually glyphosate is formulated into herbicidal compositions, preferably in water. The aforesaid copending application of Miller, Reitz and Pulwer Ser. No. 778,958 describes a method in which an aqueous solution of N-alkyl glyphosate may be prepared without isolation of intermediate by a reaction scheme commencing with N,N'-dialkyl-2,5-diketopiperazine.
Okawara et al, "Convenient Synthesis of Piperazine-2,5-diones and Lactams from Halocarboxamides Using Phase Transfer Catalysts", Chemistry Letters, 1981, pp. 185-189, describes the synthesis of various 1,4-disubstituted-2,5-diketopiperazines by intermolecular condensation of halocarboxamides using a reaction system comprising a mixture of dichloromethane and 50% aqueous sodium hydroxide solution in the presence of a solid phase transfer catalyst. Among the compounds whose synthesis are reported by Okawara et al are 1,4-dibenzylpiperazine-2,5-dione, 1,4-diphenylpiperazine-2,5-dione and 1,4-diphenyl-3,6-dimethylpiperazine-2,5-dione. The reference does not report any use for the products synthesized.
Cavicchioni et al, "Base Promoted Reactions of .alpha.-Halogeno-alkylanilides," Chem. Soc. Perkin Trans. I, pp. 2969-2972 (1982), reports the preparation of both N,N'-dialkylpiperazines and 2-amino-2-halolkyloxazolidones by intermolecular condensations of the same reactants used in the synthesis described by Okawara. Cavicchioni et al do not give much detail on the reaction system utilized but apparently employed a polar organic solvent system rather than a two-phase system comprising a phase transfer catalyst.
Wong et al U.S. Pat. No. 4,400,330 describes the preparation of bis-phosphonomethyl-2,5-diketopiperazine by phosphonomethylation of 2,5-diketopiperazine, followed by hydrolysis of the bis-phosphonomethyl-2,5-diketopiperazine to produce glyphosate. In the phosphonomethylation, formaldehyde and glacial acetic acid are added to 2,5-diketopiperazine to produce a suspension which is refluxed. Thereafter, phosphorus trichloride is added to the reaction mixture which is then maintained at reflux until all hydrogen chloride by-product has been driven off. After additional refluxing of the reaction slurry, the product is dried in vacuo, dissolved in water, and treated sequentially with caustic solution and mineral acid to effect hydrolysis and produce glyphosate.